Votrient

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Pharmacodynamics

Increases in blood pressure have been observed and are
related to steady-state trough plasma pazopanib concentrations.

The QT prolongation potential of pazopanib was assessed
in a randomized, blinded, parallel trial (N = 96) using moxifloxacin as a
positive control. Pazopanib 800 mg was dosed under fasting conditions on Days 2
to 8 and 1,600 mg was dosed on Day 9 after a meal in order to increase exposure
to pazopanib and its metabolites. No large changes (i.e., > 20 msec) in QTc
interval following the treatment of pazopanib were detected in this QT trial.
The trial was not able to exclude small changes ( < 10 msec) in QTc interval,
because assay sensitivity below this threshold ( < 10 msec) was not
established in this trial [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Absorption

Pazopanib is absorbed orally with median time to achieve
peak concentrations of 2 to 4 hours after the dose. Daily dosing at 800 mg
results in geometric mean AUC and Cmax of 1,037 mcg•hr/mL and 58.1 mcg/mL
(equivalent to 132 μM), respectively. There was no consistent increase in
AUC or Cmax at pazopanib doses above 800 mg.

Administration of a single pazopanib 400 mg crushed
tablet increased AUC(0-72) by 46% and Cmax by approximately 2 fold and
decreased tmax by approximately 2 hours compared to administration of the whole
tablet. These results indicate that the bioavailability and the rate of
pazopanib oral absorption are increased after administration of the crushed
tablet relative to administration of the whole tablet. Therefore, due to this
potential for increased exposure, tablets of VOTRIENT should not be crushed.

Systemic exposure to pazopanib is increased when
administered with food. Administration of pazopanib with a high-fat or low-fat
meal results in an approximately 2 fold increase in AUC and Cmax. Therefore,
pazopanib should be administered at least 1 hour before or 2 hours after a meal
[see DOSAGE AND ADMINISTRATION].

Distribution

Binding of pazopanib to human plasma protein in vivo was
greater than 99% with no concentration dependence over the range of 10 to 100
mcg/mL. In vitro studies suggest that pazopanib is a substrate for
P-glycoprotein (Pgp) and breast cancer resistant protein (BCRP).

Metabolism

In vitro studies demonstrated that pazopanib is
metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C8.

Elimination

Pazopanib has a mean half-life of 30.9 hours after
administration of the recommended dose of 800 mg. Elimination is primarily via
feces with renal elimination accounting for < 4% of the administered dose.

Hepatic Impairment

Mild hepatic impairment was defined as either total
bilirubin WNL with ALT > ULN or bilirubin > 1 X to 1.5 X ULN regardless of
the ALT value. The median steady-state pazopanib Cmax and AUC(0-24) after a
once daily dose of 800 mg/day in patients (N = 12) with mild impairment were 34
mcg/mL (range 11 to 104) and 774 mcg•hr/mL (range 215 to 2,034), respectively.
These were in a similar range as the median steady-state pazopanib Cma x and
AUC(0-24) in patients (N = 18) with no hepatic impairment (52 mcg/mL, range 17
to 86 and 888 mcg•hr/mL, range 346 to 1,482, respectively) [see DOSAGE AND
ADMINISTRATION].

Moderate hepatic impairment was defined as total bilirubin
> 1.5 X to 3 X ULN regardless of the ALT value. The maximum tolerated
pazopanib dose in patients with moderate impairment was 200 mg once daily. The
median (N = 11) steady-state Cmax with that regimen was 22 mcg/mL (range 4.2 to
33), and the median AUC(0-24) was 257 mcg•hr/mL (range 66 to 488). These values
were approximately 43% and 29% of the corresponding median values after
administration of 800 mg once daily in patients with normal hepatic function (N
= 18) [see DOSAGE AND ADMINISTRATION].

Severe hepatic impairment was defined as total bilirubin
> 3 X ULN regardless of the ALT value. Median exposures in patients with
severe hepatic impairment receiving 200 mg once daily (N = 14) were
unexpectedly lower than those observed in patients with moderate hepatic
impairment receiving 200 mg once daily. The median steady-state Cmax was 9.4
mcg/mL (range 2.4 to 24), and the median AUC(0-24) was 131 mcg•hr/mL (range 47
to 473). These values were approximately 18% and 15% of the corresponding
median values after administration of 800 mg once daily in patients with normal
hepatic function. Despite the observed concentrations, the dose of 200 mg was
not well tolerated in patients with severe hepatic impairment. Use of VOTRIENT
is not recommended in patients with severe hepatic impairment [see Use in
Specific Populations].

Drug Interactions

Coadministration of multiple doses of oral pazopanib 400
mg with multiple doses of oral ketoconazole 400 mg (strong CYP3A4/P-gp
inhibitor) resulted in a 1.7 fold increase in the AUC(0-24) and a 1.5 fold
increase in the Cma x of pazopanib compared to when pazopanib was administered
alone. Concurrent administration of a single dose of pazopanib eye drops with
ketoconazole in healthy volunteers resulted in a 2 fold and 1.5 fold increase
in mean AUC(0-t) and Cma x values, respectively [see DOSAGE AND
ADMINISTRATION and DRUG INTERACTIONS].

Administration of 1,500 mg lapatinib, a substrate and
weak inhibitor of CYP3A4, Pgp, and BCRP, with 800 mg pazopanib resulted in an
approximately 50% to 60% increase in mean pazopanib AUC(0-24) and Cma x compared
to administration of 800 mg pazopanib alone.

In vitro studies with human liver microsomes showed that
pazopanib inhibited the activities of CYP enzymes 1A2, 3A4, 2B6, 2C8, 2C9,
2C19, 2D6, and 2E1. Potential induction of human CYP3A4 was demonstrated in an
in vitro human PXR assay. Clinical pharmacology studies, using pazopanib 800 mg
once daily, have demonstrated that pazopanib does not have a clinically
relevant effect on the pharmacokinetics of caffeine (CYP1A2 probe substrate),
warfarin (CYP2C9 probe substrate), or omeprazole (CYP2C19 probe substrate) in
cancer patients. Pazopanib resulted in an increase of approximately 30% in the
mean AUC and Cmax of midazolam (CYP3A4 probe substrate) and increases of 33% to
64% in the ratio of dextromethorphan to dextrorphan concentrations in the urine
after oral administration of dextromethorphan (CYP2D6 probe substrate).
Coadministration of pazopanib 800 mg once daily and paclitaxel 80 mg/m²(CYP3A4
and CYP2C8 substrate) once weekly resulted in a mean increase of 26% and 31% in
paclitaxel AUC and Cmax, respectively [see DRUG INTERACTIONS].

Pazopanib exhibits pH dependent solubility. In a drug
interaction trial in patients with solid tumors, concomitant administration of
pazopanib with esomeprazole, a PPI, decreased the exposure of pazopanib by
approximately 40% (AUC and Cmax).

In vitro studies also showed that pazopanib inhibits
UGT1A1 and OATP1B1 with IC50s of 1.2 and 0.79 μM, respectively. Pazopanib
may increase concentrations of drugs eliminated by UGT1A1 and OATP1B1.

Pharmacogenomics

Pazopanib can increase serum total bilirubin levels [see WARNINGS
AND PRECAUTIONS]. In vitro studies showed that pazopanib inhibits UGT1A1,
which glucuronidates bilirubin for elimination. A pooled pharmacogenetic
analysis of 236 Caucasian patients evaluated the TA repeat polymorphism of
UGT1A1 and its potential association with hyperbilirubinemia during pazopanib
treatment. In this analysis, the (TA)7/(TA)7 genotype (UGT1A1*28/*28)
(underlying genetic susceptibility to Gilbert's syndrome) was associated with a
statistically significant increase in the incidence of hyperbilirubinemia
relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes.

Clinical Studies

Renal Cell Carcinoma

The safety and efficacy of VOTRIENT in renal cell
carcinoma (RCC) were evaluated in a randomized, double-blind,
placebo-controlled, multicenter, Phase 3 trial. Patients (N = 435) with locally
advanced and/or metastatic RCC who had received either no prior therapy or one
prior cytokine-based systemic therapy were randomized (2:1) to receive VOTRIENT
800 mg once daily or placebo once daily. The primary objective of the trial was
to evaluate and compare the 2 treatment arms for progression-free survival
(PFS); the secondary endpoints included overall survival (OS), overall response
rate (RR), and duration of response.

Of the total of 435 patients enrolled in this trial, 233
patients had no prior systemic therapy (treatment-na´ve subgroup) and 202
patients received one prior IL-2 or INFα-based therapy
(cytokine-pretreated subgroup). The baseline demographic and disease
characteristics were balanced between the VOTRIENT and placebo arms. The
majority of patients were male (71%) with a median age of 59 years. Eighty-six
percent of patients were Caucasian, 14% were Asian, and less than 1% were
other. Forty-two percent were ECOG performance status 0 and 58% were ECOG
performance status 1. All patients had clear cell histology (90%) or
predominantly clear cell histology (10%). Approximately 50% of all patients had
3 or more organs involved with metastatic disease. The most common metastatic
sites at baseline were lung (74%), lymph nodes (56%), bone (27%), and liver
(25%).

A similar proportion of patients in each arm were
treatment-na´ve and cytokinepretreated (see Table 5). In the
cytokine-pretreated subgroup, the majority (75%) had received interferon-based
treatment. Similar proportions of patients in each arm had prior nephrectomy
(89% and 88% for VOTRIENT and placebo, respectively).

The analysis of the primary endpoint PFS was based on
disease assessment by independent radiological review in the entire trial
population. Efficacy results are presented in Table 5 and Figure 1.

At the protocol-specified final
analysis of OS, the median OS was 22.9 months for patients randomized to
VOTRIENT and 20.5 months for the placebo arm [HR = 0.91 (95% CI: 0.71, 1.16)].
The median OS for the placebo arm includes 79 patients (54%) who discontinued
placebo treatment because of disease progression and crossed over to treatment
with VOTRIENT. In the placebo arm, 95 (66%) patients received at least one
systemic anti-cancer treatment after progression compared to 88 (30%) patients
randomized to VOTRIENT.

Soft Tissue Sarcoma

The safety and efficacy of
VOTRIENT in patients with STS were evaluated in a randomized, double-blind,
placebo-controlled, multicenter trial. Patients (N = 369) with metastatic STS
who had received prior chemotherapy, including anthracycline treatment, or were
unsuited for such therapy, were randomized (2:1) to receive VOTRIENT 800 mg
once daily or placebo. Patients with gastrointestinal stromal tumors (GIST) or
adipocytic sarcoma were excluded from the trial. Randomization was stratified
by the factors of WHO performance status (WHO PS) 0 or 1 at baseline and the
number of lines of prior systemic therapy for advanced disease (0 or 1 versus
2+). Progression-free survival (PFS) was assessed by independent radiological
review. Other efficacy endpoints included overall survival (OS), overall
response rate, and duration of response.

The majority of patients were
female (59%) with a median age of 55 years. Seventy-two percent of patients
were Caucasian, 22% were Asian, and 6% were other. Forty-three percent of patients
had leiomyosarcoma, 10% had synovial sarcoma, and 47% had other soft tissue
sarcomas. Fifty-six percent of patients had received 2 or more lines of prior
systemic therapy and 44% had received 0 or 1 lines of prior systemic therapy.
The median duration of treatment was 4.5 months for patients on the pazopanib
arm and 1.9 months for patients on the placebo arm. Efficacy results are
presented in Table 6 and Figure 2.